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01-02-2011 | Original Article

Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial

Authors: T. J. de Villiers, A. A. Chines, S. Palacios, P. Lips, A. Z. Sawicki, A. B. Levine, C. Codreanu, N. Kelepouris, J. P. Brown

Published in: Osteoporosis International | Issue 2/2011

Abstract

Summary

Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5 years were consistent with those seen at 3 years.

Introduction

We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis.

Methods

In the core study, healthy postmenopausal women with osteoporosis (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40 mg were transitioned in a blinded manner to bazedoxifene 20 mg (bazedoxifene 40-/20-mg group) after 4 years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere.

Results

A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium.

Conclusion

Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5 years of therapy, consistent with findings at 3 years.

North American Menopause Society (2006) Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society. Menopause 13:340–367CrossRef

Fontana A, Delmas PD (2003) Selective estrogen receptors modulators in the prevention and treatment of postmenopausal osteoporosis. Endocrinol Metab Clin N Am 32:219–232CrossRef

Dennison E, Cooper C (2000) Epidemiology of osteoporotic fractures. Horm Res 54:58–63PubMed

Atik OS, Gunal I, Korkusuz F (2006) Burden of osteoporosis. Clin Orthop Relat Res 443:19–24PubMedCrossRef

Caliri A, De Filippis L, Bagnato GL, Bagnato GF (2007) Osteoporotic fractures: mortality and quality of life. Panminerva Med 49:21–27PubMed

MacLean C, Newberry S, Maglione M, McMahon M, Ranganath V, Suttorp M, Mojica W, Timmer M, Alexander A, McNamara M, Desai SB, Zhou A, Chen S, Carter J, Tringale C, Valentine D, Johnsen B, Grossman J (2008) Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 148:197–213PubMed

Lewiecki EM (2009) Emerging drugs for postmenopausal osteoporosis. Expert Opin Emerg Drugs 14:129–144PubMedCrossRef

Arun B, Anthony M, Dunn B (2002) The search for the ideal SERM. Expert Opin Pharmacother 3:681–691PubMedCrossRef

Taylor HS (2009) Designing the ideal selective estrogen receptor modulator—an achievable goal? Menopause 16:609–615PubMedCrossRef

10.

Cranney A, Adachi JD (2005) Benefit-risk assessment of raloxifene in postmenopausal osteoporosis. Drug Saf 28:721–730PubMedCrossRef

11.

Goldstein SR, Nanavati N (2002) Adverse events that are associated with the selective estrogen receptor modulator levormeloxifene in an aborted phase III osteoporosis treatment study. Am J Obstet Gynecol 187:521–527PubMedCrossRef

12.

Shelly W, Draper MW, Krishnan V, Wong M, Jaffe RB (2008) Selective estrogen receptor modulators: an update on recent clinical findings. Obstet Gynecol Surv 63:163–181PubMed

13.

Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, McNabb MA, Wenger NK (2006) Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 355:125–137PubMedCrossRef

14.

Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A, Cummings S (2004) Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol 104:837–844PubMedCrossRef

15.

Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, Secrest RJ, Cummings SR (2004) Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 96:1751–1761PubMedCrossRef

16.

Miller PD, Chines AA, Christiansen C, Hoeck HC, Kendler DL, Lewiecki EM, Woodson G, Levine AB, Constantine G, Delmas PD (2008) Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res 23:525–535PubMedCrossRef

17.

Pinkerton JV, Archer DF, Utian WH, Menegoci JC, Levine AB, Chines AA, Constantine GD (2009) Bazedoxifene effects on the reproductive tract in postmenopausal women at risk for osteoporosis. Menopause 16:1102–1108PubMedCrossRef

18.

Silverman SL, Christiansen C, Genant HK, Vukicevic S, Zanchetta JR, de Villiers TJ, Constantine GD, Chines AA (2008) Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 23:1923–1934PubMedCrossRef

19.

Archer DF, Pinkerton JV, Utian WH, Menegoci JC, de Villiers TJ, Yuen CK, Levine AB, Chines AA, Constantine GD (2009) Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause 16:1109–1115PubMedCrossRef

20.

Silverman S, Chines A, Zanchetta JR, Genant H, Kendler D, Rio de la Loza F, Kung A, Constantine GD, Adachi J (2009) Sustained efficacy of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study. J Bone Miner Res 24 (Suppl 1). Available at: http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=2643ea2f-c4ab-4eb6-9798-09050bb21b6b. Accessed 10 Dec 2009

21.

Davies GC, Huster WJ, Lu Y, Plouffe L Jr, Lakshmanan M (1999) Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet Gynecol 93:558–565PubMedCrossRef

22.

Pfizer Inc (2008) FABLYN® (lasofoxifene tartrate) 0.5 mg tablets. NDA 22-242. Reproductive Health Drugs Advisory Committee Briefing Document, 08 September 2008. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4381b1-02-Pfizer.pdf. Accessed 10 Dec 2009

23.

Fleischer AC, Wheeler JE, Yeh IT, Kravitz B, Jensen C, MacDonald B (1999) Sonographic assessment of the endometrium in osteopenic postmenopausal women treated with idoxifene. J Ultrasound Med 18:503–512PubMed

24.

Alexandersen P, Riis BJ, Stakkestad JA, Delmas PD, Christiansen C (2001) Efficacy of levormeloxifene in the prevention of postmenopausal bone loss and on the lipid profile compared to low dose hormone replacement therapy. J Clin Endocrinol Metab 86:755–760PubMedCrossRef

25.

SmithKline Beecham (1999) SmithKline Beecham drops idoxifene for osteoporosis. SCRIP 2431:21

26.

Novo Nordisk (1998) Novo Nordisk drops levormeloxifene. SCRIP 2374:18

27.

Ronkin S, Northington R, Baracat E, Nunes MG, Archer DF, Constantine G, Pickar JH (2005) Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women. Obstet Gynecol 105:1397–1404PubMedCrossRef

28.

Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90:1371–1388PubMedCrossRef

29.

Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR, for the Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 282:637–645PubMedCrossRef

30.

Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC (1999) The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281:2189–2197PubMedCrossRef

31.

Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER Jr, Wade JL III, Robidoux A, Margolese RG, James J, Lippman SM, Runowicz CD, Ganz PA, Reis SE, Caskill-Stevens W, Ford LG, Jordan VC, Wolmark N (2006) Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2727–2741PubMedCrossRef

Title: Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial
Authors: T. J. de Villiers
A. A. Chines
S. Palacios
P. Lips
A. Z. Sawicki
A. B. Levine
C. Codreanu
N. Kelepouris
J. P. Brown
Publication date: 01-02-2011
Publisher: Springer-Verlag
Published in: Osteoporosis International / Issue 2/2011
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-010-1302-6

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Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial

Abstract

Summary

Introduction

Methods

Results

Conclusion

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Abstract

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Methods

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